Celebrating a young life that almost wasn’t

Often on the Stem Cellar we feature CIRM-funded work that is helping advance the field, unlocking some of the secrets of stem cells and how best to use them to develop promising therapies. But every once in a while it’s good to remind ourselves that this work, while it may often seem slow, is already saving lives.

Meet Ja’Ceon Golden. He was one of the first patients treated at U.C. San Francisco, in partnership with St. Jude Children’s Hospital in Memphis, as part of a CIRM-funded study to treat a rare but fatal disorder called Severe Combined Immunodeficiency (SCID). Ja’Ceon was born without a functioning immune system, so even a simple cold could have been fatal.

At UCSF a team led by Dr. Mort Cowan, took blood stem cells from Ja’Ceon and sent them to St. Jude where another team corrected the genetic mutation that causes SCID. The cells were then returned to UCSF and re-infused into Ja’Ceon.  

Over the next few months those blood stem cells grew in number and eventually helped heal his immune system.

He recently came back to UCSF for more tests, just to make sure everything is OK. With him, as she has been since his birth, was his aunt and guardian Dannie Hawkins. She says Ja’Ceon is doing just fine, that he has just started pre-K, is about to turn five years old and in January will be five years post-therapy. Effectively, Ja’Ceon is cured.

SCID is a rare disease, there are only around 70 cases in the US every year, but CIRM funding has helped produce cures for around 60 kids so far. A recent study in the New England Journal of Medicine showed that a UCLA approach cured 95 percent of the children treated.

The numbers are impressive. But not nearly as impressive, or as persuasive of the power of regenerative medicine, as Ja’Ceon and Dannie’s smiles.

Ja’Ceon on his first day at pre-K. He loved it.

CIRM-catalyzed spinout files for IPO to develop therapies for genetic diseases

Graphite Bio, a CIRM-catalyzed spinout from Stanford University that launched just 14 months ago has now filed the official SEC paperwork for an initial public offering (IPO). The company was formed by CIRM-funded researchers Matt Porteus, M.D., Ph.D. and Maria Grazia Roncarolo, M.D.

Six years ago, Dr. Porteus and Dr. Roncarolo, in conjunction with Stanford University, received a CIRM grant of approximately $875K to develop a method to use CRISPR gene editing technology to correct the blood stem cells of infants with X-linked severe combined immunodeficiency (X-SCID), a genetic condition that results in a weakened immune system unable to fight the slightest infection.

Recently, Dr. Porteus, in conjunction with Graphite, received a CIRM grant of approximately $4.85M to apply the CRISPR gene editing approach to correct the blood stem cells of patients with sickle cell disease, a condition that causes “sickle” shaped red blood cells. As a result of this shape, the cells clump together and clog up blood vessels, causing intense pain, damaging organs, and increasing the risk of strokes and premature death. The condition disproportionately affects members of the Black and Latin communities.

CIRM funding helped Stanford complete the preclinical development of the sickle cell disease gene therapy and it enabled Graphite to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA), one of the last steps necessary before conducting a human clinical trial of a potential therapy. Towards the end of 2020, Graphite got the green light from the FDA to conduct a trial using the gene therapy in patients with sickle cell disease.

In a San Francisco Business Times report, Graphite CEO Josh Lehrer stated that the company’s goal is to create a platform that can apply a one-time gene therapy for a broad range of genetic diseases.

Paving the Way

When someone scores a goal in soccer all the attention is lavished on them. Fans chant their name, their teammates pile on top in celebration, their agent starts calling sponsors asking for more money. But there’s often someone else deserving of praise too, that’s the player who provided the assist to make the goal possible in the first place. With that analogy in mind, CIRM just provided a very big assist for a very big goal.

The goal was scored by Jasper Therapeutics. They have just announced data from their Phase 1 clinical trial treating people with Myelodysplastic syndromes (MDS). This is a group of disorders in which immature blood-forming cells in the bone marrow become abnormal and leads to low numbers of normal blood cells, especially red blood cells. In about one in three patients, MDS can progress to acute myeloid leukemia (AML), a rapidly progressing cancer of the bone marrow cells.

The most effective way to treat, and even cure, MDS/AML is with a blood stem cell transplant, but this is often difficult for older patients, because it involves the use of toxic chemotherapy to destroy their existing bone marrow blood stem cells, to make room for the new, healthy ones. Even with a transplant there is often a high rate of relapse, because it’s hard for chemotherapy to kill all the cancer cells.

Jasper has developed a therapy, JSP191, which is a monoclonal antibody, to address this issue. JSP191 helps supplement the current treatment regimen by clearing all the remaining abnormal cells from the bone marrow and preventing relapse. In addition it also means the patients gets smaller doses of chemotherapy with lower levels of toxicity. In this Phase 1 study six patients, between the ages of 65 and 74, were given JSP191 – in combination with low-dose radiation and chemotherapy – prior to getting their transplant. The patients were followed-up at 90 days and five of the six had no detectable levels of MDS/AML, and the sixth patient had reduced levels. None of the patients experienced serious side effects.

Clearly that’s really encouraging news. And while CIRM didn’t fund this clinical trial, it wouldn’t have happened without us paving the way for this research. That’s where the notion of the assist comes in.

CIRM support led to the development of the JSP191 technology at Stanford. Our CIRM funds were used in the preclinical studies that form the scientific basis for using JSP191 in an MDS/AML setting.

Not only that, but this same technique was also used by Stanford’s Dr. Judy Shizuru in a clinical trial for children born with a form of severe combined immunodeficiency, a rare but fatal immune disorder in children. A clinical trial that CIRM funded.

It’s a reminder that therapies developed with one condition in mind can often be adapted to help treat other similar conditions. Jasper is doing just that. It hopes to start clinical trials this year using JSP191 for people getting blood stem cell transplants for severe autoimmune disease, sickle cell disease and Fanconi anemia.

Stem cell therapy for deadly childhood immune disorder goes four for four

The gold standard for any new therapy in the U.S. is approval by the Food and Drug Administration (FDA). This approval clears the therapy for sale and often also means it will be covered by insurance. But along the way there are other designations that can mean a lot to a company developing a new approach to a deadly disease.

That’s what recently happened with Mustang Bio’s MB-107. The therapy was given Orphan Drug Designation for the treatment of X-linked Severe Combined Immunodeficiency (SCID) also known as “bubble baby disease”, a rare but deadly immune disorder affecting children. This is the same therapy that CIRM is funding in a clinical trial we’ve blogged about in the past.  

Getting Orphan Drug Designation can be a big deal. It is given to therapies intended for the treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. It comes with some sweet incentives, such as tax credits toward the cost of clinical trials and prescription drug user fee waivers. And, if the product becomes the first in its class to get FDA approval for a particular disease, it is entitled to seven years of market exclusivity, which is independent from intellectual property protection.

This is not the first time Mustang Bio’s MB-107 has been acknowledged as a potential gamechanger. It’s also been given three other classifications both here in the US and in Europe.

  • Rare Pediatric Disease Designation: this also applies to treatments for diseases affecting fewer than 200,000 people in the US that have the potential to provide clinically meaningful benefits to patients. It provides the company with a “voucher” that they can use to apply for priority review for another therapy they are developing. The hope is that this will encourage companies to develop treatments for rare childhood diseases that might not otherwise be profitable.
  • Regenerative Medicine Advanced Therapy (RMAT) designation: this allows for faster, more streamlined approvals of regenerative medicine products
  • Advanced Therapy Medicinal Product classification: this is granted by the European Medicines Agency (EMA) to medicines that are based on genes, tissues or cells and can offer groundbreaking opportunities for the treatment of disease.

Of course, none of these designations are a guarantee that Mustang Bio’s MB-107 will ultimately get FDA approval, but they’re a pretty good indication that a lot of people have confidence they’ll get there.

Charting a new course for stem cell research

What are the latest advances in stem cell research targeting cancer? Can stem cells help people battling COVID-19 or even help develop a vaccine to stop the virus? What are researchers and the scientific community doing to help address the unmet medical needs of underserved communities? Those are just a few of the topics being discussed at the Annual CIRM Alpha Stem Cell Clinic Network Symposium on Thursday, October 8th from 9am to 1.30pm PDT.

Like pretty nearly everything these days the symposium is going to be a virtual event, so you can watch it from the comfort of your own home on a phone or laptop. And it’s free.

The CIRM Alpha Clinics are a network of leading medical centers here in California. They specialize in delivering stem cell and gene therapies to patients. So, while many conferences look at the promise of stem cell therapies, here we deal with the reality; what’s in the clinic, what’s working, what do we need to do to help get these therapies to patients in need?

It’s a relatively short meeting, with short presentations, but that doesn’t mean it will be short on content. Some of the best stem cell researchers in the U.S. are taking part so you’ll learn an awful lot in a short time.

We’ll hear what’s being done to find therapies for

  • Rare diseases that affect children
  • Type 1 diabetes
  • HIV/AIDS
  • Glioblastoma
  • Multiple myeloma

We’ll discuss how to create a patient navigation system that can address social and economic determinants that impact patient participation? And we’ll look at ways that the Alpha Clinic Network can partner with community care givers around California to increase patient access to the latest therapies.

It’s going to be a fascinating day. And did I mention it’s free!

All you have to do is go to this Eventbrite page to register.

And feel free to share this with your family, friends or anyone you think might be interested.

We look forward to seeing you there.

Celebrating a life that almost didn’t happen

Evie Vaccaro

You can’t look at this photo and not smile. This is Evie Vaccaro, and it’s clear she is just bursting with energy and vitality. Sometimes it feels like I have known Evie all her life. In a way I have. And I feel so fortunate to have done so, and that’s why this photo is so powerful, because it’s a life that almost ended before it had a chance to start.

Evie was born with a rare condition called Severe Combined Immunodeficiency (SCID). Children with this condition lack a functioning immune system so even a simple cold or diaper rash can prove fatal. Imagine how perilous their lives are in a time of COVID-19. These children used to be called “bubble babies” because they were often kept inside sterile plastic bubbles to keep them alive. Many died before their second birthday.

Today there is no need for plastic bubbles. Today, we have a cure. That’s a word we use very cautiously, but in Evie’s case, and the case of more than 40 other children, we use it with pride.

Dr. Don Kohn and a child born with SCID

Dr. Don Kohn at UCLA has developed a method of taking the child’s own blood stem cells and, in the lab, inserting a corrected copy of the gene that caused SCID, and then returning those cells to the child. Because they are stem cells they multiply and renew and replicate themselves, creating a new blood supply, one free of the SCID mutation. The immune system is restored. The children are cured.

This is a story we have told several times before, but we mention it again because, well, it never gets old, and because Evie is on the front and back cover of our upcoming Annual Report. The report is actually a look back on the last 18 months in CIRM’s life, reporting on the progress we have made in advancing stem cell research, in saving and changing lives, and in producing economic benefits for California (billions of dollars in sales revenue and taxes and thousands of jobs).  

Evie’s story, Evie’s photo, is a reminder of what is possible thanks to the voters of California who created CIRM back in 2004. Hers is just one of the stories in the report. I think,  you’ll enjoy reading all of them.

Of course, I might be just a little bit biased.

Living proof science can find a cure

Like many kids, let’s face it, many adults too, Ronav “Ronnie” Kashyap is getting a little bored stuck inside all day during the coronavirus pandemic. This video, shot by his dad Pawash, shows Ronnie trying to amuse himself by pretending to be hard at work.

https://www.instagram.com/p/B_BSQaonFXb/

It’s a lovely moment. It’s also a moment that just a few years ago seemed almost impossible. That’s because Ronnie was born with severe combined immunodeficiency (SCID). SCID kids have no functioning immune system so even a simple infection, such as a cold, can be life-threatening.

Many of those hardest hit by COVID-19 have compromised immune systems. But try fighting the virus if you have no immune system at all. The odds would not be good.

Happily, we don’t have to imagine it because Ronnie is one of around 60 children who have undergone CIRM-supported stem cell/gene therapies that have helped repair their immune system.

In Ronnie’s case he was rushed to UC San Francisco shortly after his birth when a newborn screening test showed he had SCID. He spent the next several months there, in isolation with his parents, preparing for the test. Doctors took his own blood stem cells and, in the lab, corrected the genetic mutation that causes SCID. The cells were then re-infused into Ronnie where they created a new blood supply and repaired his immune system.

How good is his immune system today? Last year his parents, Upasana and Pawash, were concerned about taking Ronnie to a crowded shopping mall for fear he might catch a cold. Their doctor reassured them that he would be fine. So, they went. The doctor was right, Ronnie was fine. However, Upasana and Pawash both caught colds!

Just a few weeks ago Ronnie started pre-school. He loves it. He loves having other kids to play with and his parents love it because it helps him burn off some energy. But they also love it because it showed Ronnie is now leading a normal life, one where they don’t have to worry about everything he does, every person he comes into contact with.

Sounds a bit like how the rest of us are living right now doesn’t it. And the fears that Ronnie’s parents had, that even a casual contact with a friend, a family member or stranger, might prove life-threatening, are ones many of us are experiencing now.

When Ronnie was born he faced long odds. At the time there were only a handful of scientists working to find treatments for SCID. But they succeeded. Now, Ronnie, and all the other children who have been helped by this therapy are living proof that good science can overcome daunting odds to find treatments, and even cures, for the most life-threatening of conditions.

Today there are thousands, probably tens of thousands of scientists around the world searching for treatments and cures for COVID-19. And they will succeed.

Till then the rest of us will have to be like Ronnie. Stay at home, stay safe, and enjoy the luxury of being bored.

Two CIRM supported studies highlighted in Nature as promising approaches for blood disorders

Blood stem cells (blue) are cleared from the bone marrow (purple) before new stem cells can be transplanted.Credit: Dennis Kunkel Microscopy/SPL

Problems with blood stem cells, a type of stem cell in your bone marrow that gives rise to various kinds of blood cells, can sometimes result in blood cancer as well as genetic and autoimmune diseases.

It is because of this that researchers have looked towards blood stem cell transplants, which involves replacing a person’s defective blood stem cells with healthy ones take from either a donor or the patient themselves.

However, before this can be done, the existing population of defective stem cells must be eradicated in order to allow the transplanted blood stem cells to properly anchor themselves into the bone marrow. Current options for this include full-body radiation or chemotherapy, but these approaches are extremely toxic.

But what if there was a way to selectively target these blood stem cells in order to make the transplants much safer?

An article published in Nature highlights the advancements made in the field of blood stem cell transplantation, some of which is work that is funded by yours truly.

One of the approaches highlighted involves the work that we funded related to Forty Seven and an antibody created that inhibits a protein called CD47.

The article discusses how Forty Seven tested two antibodies in monkeys. One antibody blocks the activity of a molecule called c-Kit, which is found on blood stem cells. The other is the antibody that blocks CD47, which is found on some immune cells. Inhibiting CD47 allows those immune cells to sweep up the stem cells that were targeted by the c-Kit antibody, thereby boosting its effectiveness. In early tests, the two antibodies used together reduced the number of blood stem cells in bone marrow. The next step for this team is to demonstrate that the treatment clears out the old supply of stem cells well enough to allow transplanted cells to flourish.

You can read more about the CD47 antibody in a previous blog post.

Another notable segment of this article is the CIRM funded trial that is being conducted by Dr. Judith Shizuru at Stanford University. This clinical trial also uses an antibody that targets c-Kit found on blood stem cells.

The purpose of this trial is to wipe out the problematic blood stem cells in infants with X-linked Severe combined immunodeficiency (SCID), a rare fatal genetic disorder that leaves infants without a functional immune system, in order to introduce properly functioning blood stem cells. Dr. Shizuru and her team found that transplanted blood stem cells, in this case from donors who did not have the disease, successfully took hold in the bone marrow of four out of six of the babies.

You can read more about Dr. Shizuru’s work in a previous blog post as well.

Good news for two CIRM-supported therapies

Jake Javier, a patient in the spinal cord injury stem cell therapy clinical trial

It’s always satisfying to see two projects you have supported for a long time do well. That’s particularly true when the projects in question are targeting conditions that have no other effective therapies.

This week we learned that a clinical trial we funded to help people with spinal cord injuries continues to show benefits. This trial holds a special place in our hearts because it is an extension of the first clinical trial we ever funded. Initially it was with Geron, and was later taken up by Asterias Biotherapeutics, which has seen been bought by Lineage Cell Therapeutics Inc.

The therapy involved transplanting oligodendrocyte progenitor cells (OPCs), which are derived from human embryonic stem cells, into people who suffered recent spinal cord injuries that left them paralyzed from the neck down.  OPCs play an important role in supporting and protecting nerve cells in the central nervous system, the area damaged in a spinal cord injury. It’s hoped the cells will help restore some of the connections at the injury site, allowing patients to regain some movement and feeling.

In a news release, Lineage said that its OPC therapy continues to report positive results, “where the overall safety profile of OPC1 has remained excellent with robust motor recovery in upper extremities maintained through Year 2 patient follow-ups available to date.”

Two years in the patients are all continuing to do well, and no serious unexpected side effects have been seen. They also reported:

– Motor level improvements

  1. Five of six Cohort 2 patients achieved at least two motor levels of improvement over baseline on at least one side as of their 24-month follow-up visit.
  2. In addition, one Cohort 2 patient achieved three motor levels of improvement on one side over baseline as of the patient’s 24-month follow-up visit; improvement has been maintained through the patient’s 36-month follow-up visit.

Brian M. Culley, CEO of Lineage Cell Therapeutics called the news “exciting”, saying “To put these improvements into perspective, a one motor level gain means the ability to move one’s arm, which contributes to the ability to feed and clothe oneself or lift and transfer oneself from a wheelchair. These are tremendously meaningful improvements to quality of life and independence.”

Evie, cured of SCID by a therapy licensed to Orchard Therapeutics

The other good news came from Orchard Therapeutics, a company we have partnered with on a therapy for Severe Combined Immunodeficiency (SCID) also known as “bubble baby diseases” (we have blogged about this a lot including here).

In a news release Orchard announced that the European Medicines Agency (EMA) has granted an accelerated assessment for their gene therapy for metachromatic leukodystrophy (MLD). This is a rare and often fatal condition that results in the build-up of sulfatides in the brain, liver, kidneys and other organs. Over time this makes it harder and harder for the person to walk, talk, swallow or eat.

Anne Dupraz-Poiseau, chief regulatory officer of Orchard Therapeutics, says this is testimony to the encouraging early results of this therapy. “We look forward to working with the EMA to ensure this potentially transformative new treatment, if approved, reaches patients in the EU as quickly as possible, and continuing our efforts to expand patient access outside the EU.”

The accelerated assessment potentially provides a reduced review timeline from 210 to 150 days, meaning it could be available to a wider group of patients sooner.  

New Report Says CIRM Produces Big Economic Boost for California

An independent Economic Impact Report says the California Institute for Regenerative Medicine (CIRM) has had a major impact on California’s economy, creating tens of thousands of new jobs, generating hundreds of millions of dollars in new taxes, and producing billions of dollars in additional revenue for the state.

The report, done by Dan Wei and Adam Rose at the Price School of Public Policy at the University of Southern California, looked at the impacts of CIRM funding on both the state and national economy from the start of the Stem Cell Agency in 2004 to the end of 2018.

The total impacts on the California economy are estimated to be:

  • $10.7 billion of additional gross output (sales revenue)
  • $641.3 million of additional state/local tax revenues
  • $726.6 million of additional federal tax revenues
  • 56,549 additional full-time equivalent (FTE) jobs, half of which offer salaries considerably higher than the state average

Maria Millan, M.D., CIRM’s President and CEO, says the report reflects the Agency’s role in building an ecosystem to accelerate the translation of important stem cell science to solutions for patients with unmet medical needs. “CIRM’s mission on behalf of patients has been the priority from day one, but this report shows that CIRM funding brings additional benefits to the state. This report reflects how CIRM is promoting economic growth in California by attracting scientific talent and additional capital, and by creating an environment that supports the development of businesses and commercial enterprises in the state”

In addition to the benefits to California, the impacts outside of California on the US economy are estimated to be:

  • $4.7 billion of additional gross output (sales revenue)
  • $198.7 million of additional state (non-Californian) & local tax revenue
  • $208.6 million of additional federal tax revenues
  • 25,816 additional full-time equivalent (FTE) jobs

The researchers summarize their findings, saying: “In terms of economic impacts, the state’s investment in CIRM has paid handsome dividends in terms of output, employment, and tax revenues for California.”

The estimates in the report are based on the economic stimulus created by CIRM funding and by the co-funding that researchers and companies were required to provide for clinical and late-stage preclinical projects. The estimates also include:

  • Investments in CIRM-supported projects from private funders such as equity investments, public offerings and mergers and acquisitions,
  • Follow-on funding from the National Institutes of Health and other organizations due to data generated in CIRM-funded projects
  • Funding generated by clinical trials held at CIRM’s Alpha Stem Cell Clinics network

The researchers state “Nearly half of these impacts emanate from the $2.67 billion CIRM grants themselves.”

“The economic impact of California’s investment in stem and regenerative cell research is reflective of significant progress in this field that was just being born at the time of CIRM’s creation,” says Dr. Millan. “We fund the most promising projects based on rigorous science from basic research into clinical trials. We partnered with researchers and companies to increase the likelihood of success and created specialized infrastructure such as the Alpha Clinics Network to support the highest quality of clinical care and research standards for these novel approaches.  The ecosystem created by CIRM has attracted scientists, companies and capital from outside the state to California. By supporting promising science projects early on, long before most investors were ready to come aboard, we enabled our scientists to make progress that positioned them to attract significant commercial investments into their programs and into California.”

These partnerships have helped move promising therapies out of the lab and into clinical trials for companies like Orchard Therapeutics’ successful treatment for Severe Combined Immunodeficiency and Forty Seven Inc.’s innovative approach to treating cancer.

Dr. Don Kohn: Photo courtesy UCLA Jonsson Comprehensive Cancer Center

“I think one of the greatest strengths of CIRM has been their focus on development of new stem cell therapies that can become real medicines,” says UCLA and Orchard Therapeutics’ Don Kohn, M.D. “This has meant guiding academic investigators to do the things that may be second nature in industry/pharmaceutical companies but are not standard for basic or clinical research.  The support from CIRM to perform the studies and regulatory activities needed to navigate therapies through the FDA and to form alliances with biotech and pharma companies has allowed the stem cell gene therapy we developed to treat SCID babies to be advanced and licensed to Orchard Therapeutics who can make it available to patients across the country.”

Dr. Mark Chao: Photo courtesy Forty Seven Inc.

“CIRM’s support has been instrumental to our early successes and our ability to rapidly progress Forty Seven’s CD47 antibody targeting approach with magrolimab,” says Mark Chao, M.D., Ph.D., Founder and Vice President of Clinical Development at Forty Seven Inc. “ CIRM was an early collaborator in our clinical programs, and will continue to be a valued partner as we move forward with our MDS/AML clinical trials.”

The researchers say the money generated by partnerships and investments, what is called “deal-flow funding”, is still growing and that the economic benefits created by them are likely to continue for some time: “Deal-flow funding usually involves several waves or rounds of capital infusion over many years, and thus is it expected that CIRM’s past and current funding will attract increasing amounts of industry investment and lead to additional spending injections into the California economy in the years to come.”

They conclude their report by saying: “CIRM has led to California stem cell research and development activities becoming a leader among the states.”